Influence Of RhBNP On No-reflow In Pigs And Ventricular Remodeling And Systolic Synchrony In Patients With Acute Myocardial Infarction Performed PCI

Acute myocardial infarction(AMI),which includes a series of clinical manifestation, induces ischemia and necrosis of myocardium because of the epicardial artery total occlusion. At present, to reopen the infarct related artery by percutaneous coronay intervention (PCI) is the most effective and direct method in the treatment of AMI, which can improve obviously the clinical prognosis of patients with AMI. Recent years, studies showed that as soon as the epicardial artery occluded, the arteriole and capillary will be damaged seriously, in these patients, although the lumen of IRA were reopened with residual stenosis less than 10%, the distal ischemic area of IRA still existed antegrade blood flow disorder(TIMI≤2), this phenomenon was called slow reflow phenomenon (SRP) or no reflow phenomenon(NRP)It was reported that NRP occurred in about 10-30% AMI patients treated by PCI. In nature, NRP is invalid reperfusion. The ischemic damage of tissue was continued and aggravated by the damage caused by NRP. When NRP happened, the myocardium can not get valid blood supply. NRP will induce serious hemodynamic disorder, which will lead deterioration of heart function even the occurrence of cardiac events such as ventricular fibrillation, cardiac arrest and so on.NRP can ten times increase the incidence rate of death, reinfarction and malignant arrhythmia. It also can increase the incidence rate of acute or chronic heart failure. NRP affects seriously the improvement of heart function and long term prognosis.The judgment and definition of NRP in clinical is the premise to prevent and treat it. The evaluation of cardiac tissue perfusion according to the TIMI blood flow grading exists obvious limitation while TIMI frame counts(TFCs) and TIMI myocardial perfusion grading(TMPG) could reflect objectively the level of myocardial tissue perfusion, which might be a simple and feasible way to evaluate the cardiac tissue perfusion. Intracoronary administration of pressure wire and flow wire to monitor the pressure of proximal and distal of coronary artery and blood flow maybe a superior method to evalue the tissue perfusion of myocardium.NRP may be the result of interaction of many factors, the mechanism of which is complex.When NRP happened, the microvascular system suffered from serious damage.The resistance of microcirculation was increased.Brain natriuretic peptide can obviously dilate the epicardial artery and resistant vessel of coronary artery, increase the coronary blood flow, reduce the resistance of coronary and increase the perfusion pressure of coronary artery. The purpose of this study is that based on the establishing of NRP model with AMI in Yorkpigs, the changes of TMPG, TFCs, hemodynamics, as well as the effect on myocardial infarction size have been observed and monitored after intracoronary administration of rhBNP. As a result, it will offer experimental foundation for clinical application to prevent and treat NRP. On the another hand, the aim of clinical study is to explore the effect, safety and feasibility of intracoronary administration of rhBNP in increasing coronary blood volume, decreasing the resistance of coronary artery, inhibiting the remodeling of left ventricle, preventing and treating of NRP after PCI .Heart function and ventricular remodeling were evaluated after intracoronary administration of rhBNP via single photo emission computer tomography(SPECT), equilibrium radionuclide angiography(ERNA) and ultrasonic cardiogram(UCG). Present study is composed of three aspects as described as follows:PartⅠThe study of establishing no-reflow model in AMI Yorkpigs by percutaneous balloon-occlusion and intracoronary injection of sterile microembolusObjective: This study was aimed to probe the feasibility of establishing no-reflow model in AMI Yorkpigs by balloon-occlusion-reperfusion- intracoronary injection of sterile microembolus via superselecting left anterior descending branch. Methods: 12 capita of Yorkpigs, 3-5 months old, were enrolled in this study. Left and right coronay angiography (CAG) were performed with 4F JL3.5 and JR4.0 catheter, then LAD were superselected with 6F guiding catheter. A balloon was set at middle segment of LAD and inflated for 90 minutes. After deflating of the balloon, the sterile microembolus was injected into LAD intermittently. The coronary flow state and level of myocardial perfusion were evaluated by TIMI frame count(TFC), TIMI myocardial grade( TMPG) and intracoronary flow and pressure Doppler monitor. TIMI flow grade≤2 ,TMPG≤1or TFC﹥36.2 frame was as the success criteria of setting up model of no reflow phenomenon with AMI.Left ventroiculography were performed with 4F pigtail , left ventricular diastolic pressure (LVEDP) left and ventricular systolic pressure(LVS.P) were monitored and recorded.The pressure of aorta and distal of LAD were monitor and recorded with pressure wire,while the average peak velocity(APV) and the ratio of diastolic and systolic peak velocity of LAD were measured with flow wire, and ComboMap System Model 6800. Mean right atrial pressure, mean right ventricular pressure,mean pulmonary artery pressure and pulmonary capillary wedge pressure and cardiac output were measured with 5F Swan-Ganz catheter.The changes of ECG and blood pressure were monitored.Blood samples were taken from coronary artery at 5,60 and 120 minutes to measure the myocardial necrosis marker(CK-MB and TNI) .Results:(1)There were 9 Yorkpigs survived after successfully no reflow phenomenon model maken.The success rate of modle making was 75%.The average time of injecting microembolus was 3.2±0.6. (2) The ECG showed ST segment elevation and shaped into single vector curve with T wave,then R wave become smaller gradually.(3)cTnI and CK-MB were all increased compared with that before the injection of microembolus[(CK-MB 149.89±26.68ng/ml vs. 19.13±3.94ng/ml) , (cTnI 110.14±21.08ng/ml vs. 16.41±3.61ng/ml)](.4)The values of PAP,PCWP,LVEDP and heart rate were increased, while LVSP was decreased significantly at instant, 30,60 and 120 minutes after NRP compared with that of baseline(P<0.05).(5) APV was decreased from 25.24±3.64cm/s of baseline to 18.51±4.52 cm/s when NRP happened,and DSVR decreased from 2.23±0.74 to 2.15±1.14.The coronary blood flow(CBF) was decreased from 30.09±13.45ml/min to 20.65±11.29ml/min, and the coronary resistance(CR) was increased from 4.12±0.92 mmHg·min/ml to 4.74±0.63 mmHg·min/ml. The mean coronary pressure became lowered from 129.9±19.7 mmHg of baseline to Pa105.2±13.0mmHg and Pd106.0±11.8 mmHg when NRP happened.The changes of proximal and distal coronary pressure were almost the same.Conclusion: With 4F catheter-based skills and balloon occlusion /reperfusion/sequential injection of microemboli blood suspension by superselecting LAD in the large scale angiography machine, the model of NRP with AMI could be established in Yorkpigs whose heart anatomy and characteristics of coronary artery were more similar to human being. Compared with myocardium dyeing and other methods, there are several advantages in this model: direct viewing, simplicity, repetitiveness, mild trauma, closed chest, high achievement ratio and more similar to NRP after PCI in clinicl. It might provide better experimental animal model for microcirculation disturbance after AMI.Part II: Evaluation of rhBNP`s Reverse Effect on No-Reflow Phenomenon after Acute Myocardial Infarction with Intracoronary Doppler Wire Objective: Based on the coronay artery stenosis and no-reflow model of Yorkpigs, through intracoronary Doppler wire and TMPG, to investigate the effect of intracoronary administration of rh-BNP on coronay blood flow especially no-reflow phenomenon and systemic hemodynamics to provide evidence for clinic use.Methods: Total of 12 Yorkpigs (3-5 months old ) were included in this study, 24μg adenosine was"bolus"injected into left coronary artery before the balloon totally inflated in order to measure CFR. Coronary blood flow was recorded with intracoronary Doppler wire before and after administration of rhBNP. 10 Yorkpigss with stable NRP were divided into adenosine group(n=5)and BNP group(n=5). Left and right coronary angiography was performed with 4F micro-catheter technique to observe the distribution and shape of coronary artery. After the NRP models were established,24μg adenosine or BNP 0.5μg/kg was injected respectively into coronary artery in the two groups. The changes of blood flow were observed at 1,3,5,10 and 15 minutes after injection. Coronary blood flow velocity was recorded by TFCs, TMPG. Quantitative measurement of diameter was recorded by the assisting quantitative coronary analysis system (QCA). MRAP, mRVP, mPAP and PCWP were monitored by Swan-Ganz floating catheter. The changes of APV were measured by intracoronary Doppler wire, CBF and CR were caculated according to the following formula:CBF(ml/min)=π(D2/4)(APV/2)(0.6), CR(mmHg. min/mL)=(MAP-mRAP)/CBF.Results: (1) Influence of rhBNP on parameters of coronary function and hemodynamics in coronary stenosis model of Yorkpigss When balloon occlude incompletely, CFR was 2.62±0.68 measured before administration of rhBNP. APV increased from 21.8±5.72 cm/s at baseline to the peak value (34.3±3.92cm/s) 5 minutes after intracoronary injection of BNP, which was increased by57.34%( P <0.05). The diameter of coronary artery and CBF were increased from (2.26±0.53mm, 26.22±13.45ml/Hg) at baseline to peak volume (2.42±0.46mm, 46.62±14.47ml/Hg)at 15 minutes after administration BNP, which were increased by7.08% and 77.80% respectively(P<0.05). The values of MAP, MRAP and CR were decreased from 26.22±13.45mmHg, 6.39±1.34mmHg and 3.21±0.92 mmHg·min/ml to the lowest values (84.45±13.26mmHg, 4.63±1.23 mmHg, 1.71±0.65mmHg*min/ml) after 15 minutes, which were decreased by 6.63%,27.54%,46.73% respectively(P<0.05). (2) Effect of intracoronary administration of rhBNP and adenosine on hymodynamics parameters in NRF model: BNP group: The values of MRAP, MPAP, PCWP, MAP ,HR were decreased by 29.17%, 23.44%, 9.79% 5.76% 6.8% respectively 15 minutes after administration BNP,from baseline (6.41±1.51mmHg, 18.73±4.33 mmHg, 15.32±2.34 mmHg, 90.32±15.63mmHg, 147±11bpm) to (4.54±1.28mmHg, 14.34±3.24 mmHg, 13.82±4.2 mmHg, 85.12±13.44mmHg, 137±18bpm) (P<0.05). adenosine group:The values of MRAP,MPAP,PCWP,MAP,HR had no significant difference compared with that at baseline.(3) Influence of intracoronary administration of rhBNP and adenosine on parameters of coronary function in NRF model rhBNP group: Coronary artery diameter and CBF were increased gradually and after 15 minutes reached the peak volume(from 2.27±0.62mm,20.78±7.02 ml/min at baseline to 2.38±0.72mmHg,35.94±4.99 ml/min, which were increased by 4.85%, 72.95% respectively(P<0.05). CR was decreased from 4.04±2.22 mmHg?min/ml at baseline to 2.27±1.98mmHg?min/ml,which was decreased by 77.97%, (P<0.05). APV was increased by57.36% and reached peak volume (26.94±7.17cm/s) 10 minutes after coronary administration of rhBNP(P<0.05). Adenosine group: The values of coronary diameter changed were the most at 1 and 3 minutes after intracoronary administration of adenosine, which were increased by 6.70%,7.59% respectively compared with the value of baseline(2.24±0.53mm), as compared with that of baseline the difference was significant but no significant difference compared with the peak value in BNP group at 15 minutes. CBF and APV were increased by 137.53% and105.18% respectively to peak values(52.59±5.68 ml/min,38.45±5.12 cm/sec)at 3 minutes after the administration of adenosine (compared with that at baseline,p<0.05), which were significantly improved as compared with that of the same period in BNP group. CR was decreased by58.90% to the lowest level (1.57±2.14mmHg.min/ml) 3 minutes after administration of adenosine ( P<0.05), which had statistical significance compared with that of the peak value in rhBNP group.(4) Effect on TFC and TMPG of intracoronary administration of rhBNP and adenosine. BNP group: At 1,3,5,10and 15 min after administration of BNP, the values of TFC were 49.33±4.1,48.24±3.4,47.51±4.9,44.23±2.4,45.42±5.9,which were decreased by 38.52%, 39.88%, 40.79%, 44.88%, 43.39%respectively compared with the baseline(80.24±7.1) (P<0.05). TIMI flow grade was obtained grade 3 only one pig (1/5) , but the grade in TMPG was≤1 in all the 5 pigs. Adenosine group:At 1,3,5,10and 15 minutes after administration adenosine, the values of TFC were 36.33±7.1, 35.14±8.1, 34.53±7.2, 32.33±7.6, 33.22±7.5, which were decreased by 55.27%, 56.75%, 57.50%, 60.21%, 59.11% respectively compared with that of the baseline(81.25±6.8)(P<0.05). TIMI flow grade reached grade 3 in three pigs (3/5) and TMPG reached grade 2 in all the five pigs, which had significant difference compared with that in rhBNP group.Conclusion:1 Intracoronary administration of rhBNP can dilate the large coronary vessel and the resistance vessel, decrease the coronary resistance, increase the coronary blood flow. 2 Intracoronary administration of rhBNP can decrease the TFC, but can not reverse the no-reflow phenomenon.Part 3 Influence of intravenous administration of rhBNP on ventricular remodeling and left ventricular function in patients with acute myocardial infarction performed PCIObjective: This study was aimed to investigate the infuence of rhBNP based on routine treatment on inhibiting ventricular remodeling, improving left heart function and ameliorating the prognosis by 99mTc-MIBI myocardial perfusion image, equilibrium radionuclide angiography and ultrasound cardiography in patients with acute myocardial infarction performed PCI Methods: Total of 48 cases of patients(male 33cases, female 15 cases; mean age54.8±6.3yrs) with acute myocardial infarction were enrolled in this study.Among them ,25 cases in rhBNP group and 23 cases in control group.There was no significant difference between the two groups in age, sex,risk factors, blood pressure level, Killip heart function grade,time from onset to balloon and the peak value of CK-MB or CK. Ultrasound cardiography was performed at 1,4 and 24 weeks after PCI respectively to obtain the parameters of myocardial remodeling such as LVEDVI,LVESVI,LVMI.There were 12 patients in each group performed 99mTc–MIBI myocardial perfusion image and ERNA..99mTc-MIBI 740MBq were intravenously injected before PCI, then patients were performed single photon emission computed tomography ( SPECT ) at rest as baseline control. 99mTc-MIBI SPECT at rest was repeated at 1 week after PCI to observe the changes of parameters such as ES,?S,U?S/Umax. ERNA was performed within 24 hours,at 1 week and 24 weeks after PCI to evaluate the changes of systolic function parameters (LVEF,LVPER,LVTPER),diastolic function parameters (LVPFR, LVTPFR) and systolic synchrony parameters (PS,FWHM,PSD).Results: (1) Comparison of the systolic function parameters between rhBNP group and control group The parameters of left ventricular systolic function at baseline were no significant difference between rhBNP group and the control group. At 1 week after PCI, LVEF and LVPER increased, LVTPER decreased significantly in two groups (41.42±3.26%, vs. 37.98±3.42%, 1.60±0.07EDV/s vs. 1.38±0.05EDV/s, 178±17 ms vs. 216±25ms P<0.01 in rhBNP) (40.88±3.47% vs. 36.92±3.79%, 1.59±0.10EDV/s vs. 1.40±0.08EDV/s , 184±11ms vs. 218±14ms in control group,P<0.01),but no statistic difference between two groups. Above parameters were further improved at 6 months compared with that at 1 week in both of two groups (50.45±6.23% vs. 41.42±3.26%, 2.68±0.11EDV/s vs. 1.60±0.07EDV/s, 151±16 ms vs. 178±17 ms,P<0.01 in rhBNP group),(45.14±4.56% vs. 40.88±3.47%,2.18±0.14EDV/s vs. 1.59±0.10EDV/s, 168±15 ms vs. 184±11 ms,P<0.01 in control group),and the improvement in rhBNP group was better than that in control group. (2) Comparison of the diastolic function parameters between rhBNP group and control group The left ventricular diastolic function parameters(LVPFR,LVTPFR) were no significant difference between the two groups at baseline. At 1 week after PCI, LVPFR increased, LVTPFR decreased significantly in two group(1.76±0.21EDV/s vs. 1.54±0.23EDV/s,202±25 ms vs. 232±24ms P<0.01 in rhBNP group)(1.71±0.43EDV/s vs. 1.52±0.20EDV/s,209±28ms vs. 234±30ms,P<0.01 in control group), but no statistic difference between the two groups. Above parameters were further improved at 6 months compared with that at 1 week in both of two groups (2.38±0.33EDV/s vs. 1.76±0.21EDV/s, 164±15 ms vs. 202±25 ms,P<0.01 in rhBNP group) (2.36±0.15EDV/s vs. 1.71±0.43EDV/s,170±22 ms vs. 209±28 ms, P<0.01 in contol group), but no statistic difference between the two groups. (3) Comparison of the systolic synchrony parameters between rhBNP group and control group The systolic synchrony parameters (PS,FWHM, PSD) were no significant difference between the two groups at baseline. At 1 week after PCI, PS, FWHM, PSDdecreased significantly in two groups (68.73±22.47°vs.74.27±28.54°, 31.62±12.48°vs. 36.54±19.36°,14.14±4.26°vs. 16.26±3.32°,P<0.01 in rhBNP group)(70.33±34.56°vs. 75.91±39.04°, 33.12±13.54°vs. 37.07±15.79°, 14.94±3.45°vs. 15.98±4.56°,P<0.01 in control group), but no statistic difference between the two groups. Above parameters were further improved at 6 months compared with that at 1 week in both of two groups(41.92±16.75°vs. 68.73±22.47°,19.53±5.66°vs. 31.62±12.48°,9.14±1.28°vs. 14.14±4.26°,P<0.01 in rhBNP group)(53.16±20.36°vs. 70.33±34.56°,25.85±8.36°vs. 33.12±13.54°,11.77±2.34°vs. 14.94±3.45°,P<0.01 in control group) and the improvement in rhBNP group was better than that in control group. (4) Comparison of the parameters of ventricular remodeling between rhBNP group and control group. The parameters of ventricular remodeling (LVESVI,LVEDVI,LVMI) at 1 week after PCI were no significant difference between the two groups. LVESVI, LVEDVI and LVMI were improved at 4 weeks after PCI compared with that at 1 week in both of the two groups(40.74±4.93ml/m2 vs. 51.23±6.58ml/m2, 67.51±6.24ml/m2 vs. 83.48±14.37ml/m2, 121.87±5.48g/m2 vs. 132.75±11.58g/m2, P<0.05 in rhBNP group)(46.49±5.87ml/m2 vs. 53.46±6.22 ml/m2 , 79.98±15.11ml/m2 vs. 87.94±12.67ml/m2 ,124.72±13.41g/m2 vs. 136.84±12.47 g/m2,P<0.05 iin control group). LVESVI and LVEDVI were more decreased in rhBNP group than that in control group, while the change of LVMI at 4 weeks was no significnat difference between the two groups.The values of LVESVI,LVEDVI,LVMI in rhBNP group were more decreased at 6 months after PCI compared with that of 4 weeks after PCI (25.86±4.34ml/m2 vs. 40.74±4.93ml/m2,53.47±4.71ml/m2 vs. 67.51±6.24ml/m2,106.57±7.26g/m2 vs. 121.87±5.48g/m2,P<0.05),these changes of LVESVI,LVEDVI also were found in the control group (32.68±4.72ml/m2 vs. 46.49±5.87ml/m2,62.61±9.96ml/m2 vs.79.98±15.11 ml/m2,P<0.05), but the change of LVMI in control group at 6 months after PCI was no statistic significance compared with that 4 week after(119.20±11.86g/m2 vs. 124.72±13.41g/m2 ,P>0.05). The advantage in rhBNP group grew more compared between two group at 6 months after PCI with that 4 weeks after PCI. 5 Comparison of the results of SPECT between rhBNP group and control group The values of ES and U?S/Umax were no significant difference between rhBNP and control group before PCI(0.56±0.08 vs. 0.55±0.11,28.33±6.77 vs. 29.26±6.38,P >0.05). The improvement of ES and U?S/Umax was larger in rhBNP group compared with that of control group 1 week after PCI compared with that before PCI (0.28±0.06 vs. 0.56±0.08,51.26±5.76 vs. 28.33±6.77,P<0.05 in rhBNP group) (0.43±0.07 vs. 0.55±0.11,42.13±9.26 vs. 29.26±6.38,P<0.05 in control group).Conclusions: 1. Administration of rhBNP based on the PCI may further alleviate the myocardial damage and decrease the infarction area compared with the routine treatment after PCI. 2. Administration of rhBNP based on the PCI may further decrease the acute left ventricular remodeling, improve the left ventricular function and left ventricular systolic synchrony compared with that of routine treatment after PCI.